Nicotine salts having improved taste, process for their preparation and their use

ABSTRACT

Salts formed from nicotine and anion-forming sweeteners, for example acesulfame or acesulfame-K, in a molar ratio of 1:1 or 1:2, in which case the sweetener molecules can be identical or different, are distinguished by a pleasant sweet taste which masks the nicotine taste even after a long residence time in the mouth, and are therefore suitable for producing preparations, in particular chewing gum, chewing tablets or compressed compositions, which can be used for oral administration of nicotine, for example in withdrawal from smoking.

BACKGROUND OF THE INVENTION

[0001] Owing to continuous consumption of cigarettes, smokers arehabituated to regularly taking nicotine. Because of the disadvantageouseffects of smoking on health, many smokers are interested in giving upsmoking.

[0002] This intention however fails in many cases owing to the fact thatthe regular consumption of nicotine has already led to a physicaldependency. For slow withdrawal, various routes have been proposed, forexample applying nicotine to the skin in the form of impregnatedplasters or supplying it orally, for example via a chewing gum (U.S.Pat. No. 5,488,962). Supply via chewing gum additionally has theadvantage that the oral intake compensates for the need for suckingcigarettes.

[0003] However, nicotine has a taste which, when consumed alone, isperceived as unpleasant. It is generally described as sharp topepper-like and bitter. This unpleasant taste hinders the acceptance ofchewing gum with added nicotine which should be chewed regularly forwithdrawal from smoking, particularly in the initial phase. In order toimprove the acceptance of nicotine-containing chewing gums or otherpreparations which can be consumed orally, there is therefore therequirement for improving or masking the unpleasant taste of nicotine.

[0004] There have been a whole series of attempts to mask the unpleasanttaste of nicotine. The use of flavoring substances and taste substancessuch as peppermint or strawberry flavorings has not previously led tosatisfactory masking of the nicotine taste. Only the use of theinclusion compounds, for example with cyclodextrins (WO 97/41843) issuitable to date for inducing an improvement in taste. However, suchinclusion compounds alone do not lead to sufficient taste acceptance,rather additional taste substances must be used, for example in chewinggum.

[0005] Therefore, the manufacturers of nicotine chewing gums havealready attempted to mask the unpleasant taste of nicotine bycombination with sweeteners, generally saccharin and/or acesulfame-K,which are incorporated into the chewing gum base mass. The sweeteners assuch, however, cannot mask the nicotine taste, so that the nicotinetaste during the chewing taste becomes increasingly more clearlyperceptible and becomes more clearly pronounced with the chewingprocess.

[0006] This taste impression of the abovementioned mixtures can bereproduced by simple sensory experiments with aqueous solutions, sinceboth nicotine and the sweeteners are water soluble. For this purpose,solutions of nicotine containing various sweeteners such asacesulfame-K, saccharin sodium or aspartame are prepared in water and ataste sample is compared with a nicotine-containing aqueous solution (10mg of nicotine in 100 ml of water). The various combinations of nicotinewith each of the sweeteners and the corresponding taste impressions areshown in table 1. TABLE 1 Taste testing of the combination of nicotinewith sweeteners mg of dissolved substance in 100 ml of Substances waterNicotine 10 10 10 10 10 Ace- — 12 24 12 12 sulfame-K Saccharin — — — 15— Na Aspartame — — — — 15 Taste Immedi- Immedi- Immedi- Immedi- Immedi-ately ately ately ately ately pepper- pepper- pepper- pepper- pepper-like, like, like, like, like, rough, rough, rough, rough, rough, persis-persis- persis- persis- persis- tent tent tent tent tent unplea- unplea-unplea- unplea- unplea- santly santly santly santly santly bitter bitterbitter bitter bitter taste taste taste taste taste with with with withaccom- accom- bitter accom- panying panying and panying slight strongersweet slight sweet sweet after- sweet taste taste taste taste

[0007] The results verify that the unpleasant taste of nicotine is notsubstantially modified by simple addition of the abovementionedsweeteners. Therefore, there is still the requirement for masking theunpleasant taste of nicotine in preparations which are taken orally, inparticular in chewing gum, during the chewing process.

[0008] WO 99/04822 describes 1:1 salts of a sweetener and anunpleasantly tasting pharmaceutical. Salts of an anionic sweetener andnicotine are not described.

[0009] WO 00/12067 describes 1:1 salts of saccharin with syntheticnon-alkaloidal medicinal organic bases. Salts of an anionic sweetenerand nicotine are not described.

[0010] EP-B 0 046 506 describes Vincamine saccharinate and medicamentscontaining this. Salts of an anionic sweetener and nicotine are notdescribed.

[0011] It has now been found that nicotine, owing to its basiccharacter, can react with anion-forming substances, which are present inthe form of their corresponding acid, to give salt-like compounds.

[0012] Not only are salts prepared here from one molecule of nicotineand one molecule of sweetener, but also defined compounds of onemolecule of nicotine and two molecules of sweetener may be prepared, inwhich even two different sweeteners can be used. Surprisingly, all ofthese compounds are distinguished by a pleasant sweet taste, from whichthe unpleasant components of nicotine are substantially absent. Theyconsist only of components which are used in any case, for example innicotine- containing chewing gums, and make further working steps, suchas the preparation of inclusion compounds mentioned in WO 97/41843,superfluous. Thus this invention is an important advance in theproduction, composition and use of nicotine-containing preparations forwithdrawal from smoking.

BRIEF DESCRIPTION OF THE INVENTION

[0013] The present invention thus relates to compounds or salts ofnicotine and anion-forming sweeteners or their physiologicallyacceptable salts or sweeteners which have acid character in free form,or their physiologically acceptable salts. These compounds can also bepresent as what are termed acid-addition salts, preferably with HCl, orother physiologically acceptable acids, for example acetic acid orsulfuric acid.

DETAILED DESCRIPTION OF THE INVENTION

[0014] Suitable compounds for the preparation of these compounds are inprinciple all sweeteners or their physiologically acceptable salts, suchas in particular the potassium salt of acesulfame (acesulfame-K), whichare able to form anions, including in particular

[0015] acesulfame and other oxathiazinone sweeteners

[0016] alitame

[0017] aspartame and aspartame-like di- and tripeptides

[0018] cyclamate and other sulfamate sweeteners

[0019] glycyrrhizin

[0020] neotame

[0021] saccharin

[0022] gluconic acid

[0023] Acesulfame (acesulfame-H) and acesulfame-K are particularlypreferred.

[0024] A multiplicity of combinations are possible here, in particularin the case of the compounds of one molecule of nicotine and twosweetener molecules. By suitable choice of the sweeteners, in particularin compounds having two different sweeteners, surprisingly the sweettaste may be modified, in particular the perception of sweetness withtime, firstly with respect to masking the nicotine taste, secondly forsetting an optimum overall taste impression. This is a criticaladvantage compared with the 1:1 compounds of 1 mol of sweetener and 1mol of nicotine.

[0025] The present invention thus also relates to a process forpreparing the inventive nicotine-sweetener compounds by reactingnicotine with sweeteners in the form of their free acids (for exampleacesulfame-H) in a suitable solvent. Suitable solvents are preferablywater and/or water-miscible solvents, for example alcohols. Sweetenerssuitable for this direct reaction are preferably acesulfame, cyclamate,glycyrrhizin, gluconic acid and/or saccharin. A process variant is thatthe sweeteners or their salts (for example acesulfame-K) are reactedwith nicotine in a solvent as described above in the presence of aphysiologically harmless acid, preferably hydrochloric acid, or othersuitable inorganic or organic acids, for example acetic acid or sulfuricacid, and the resultant acid addition salts (cf., for example,diagram 1) of the nicotine-sweetener compounds are isolated.

[0026] The starting materials for the preparation of the inventivecompounds are commercially available or can be prepared according tomethods known from the literature; for example acesulfame/acesulfame-Kcf. EP-A 0 155 643.

[0027] The nicotine-sweetener compounds, salts or adducts are obtainedvery simply from solutions, preferably from aqueous solutions, ofnicotine and the corresponding acid of the respective sweetener or, forexample in a hydrochloric acid solution of the respective sweetener, asshown in the examples below, in particular for acesulfame-H. Theresulting reaction solutions are freed from the solvent in a suitablemanner, for example under reduced pressure. The nicotine-sweetenercompounds, according to ¹H-NMR are present as 1:1, preferably as 1:2 or1:1:1 adducts. To prepare compounds without additional salt content (noacid addition salts), preferably those sweeteners are used which areacids in the free form.

[0028] The invention further relates to the use of said compounds forpreparing solid or liquid preparations which are suitable for oralsupply of nicotine, preferably in the form of chewing gum, chewingtablets, compressed compositions or similar preparations. In addition,general preparations which comprise the inventive compounds are includedby the invention.

[0029] The examples below are intended to describe the invention in moredetail without restricting its scope.

EXAMPLE 1

[0030] Preparation of a 1:1 salt of nicotine and acesulfame-H (cf.diagram 1)

[0031] 20 mmol (3.244 g) of nicotine are dissolved in 20 ml of water and20 mmol (3.263 g) of acesulfame-H are added. The reaction mixture isthen concentrated under reduced pressure. A yellow-brown oil resultswith 100% yield, which according to ¹H-NMR is present as 1:1 adduct.

EXAMPLE 2

[0032] Preparation of a 1:1:1 salt of nicotine, acesulfame-H andsaccharin-H (cf. diagram 2)

[0033] 20 mmol (3.244 g) of nicotine are dissolved in 20 ml of water and20 mmol (3.263 g) of acesulfame-H are added. Then a further 20 mmol(3.664 g) of saccharin-H are added. The reaction mixture is thenconcentrated under reduced pressure. A yellow-brown oil results with100% yield which according to ¹H-NMR is present as 1:1:1 adduct.

EXAMPLE 3

[0034] Preparation of a 1:2 salt of nicotine and acesulfame-H (cf.diagram 2)

[0035] 20 mmol (3.244 g) of nicotine are dissolved in 20 ml of water and40 mmol (6.526 g) of acesulfame-H are added. The reaction mixture isthen concentrated under reduced pressure. A yellow amorphous solidresults with 100% yield which according to ¹H-NMR is present as 1:2adduct.

[0036] The various nicotine-sweetener compounds in a molar ratio of 1:1and 1:2 or 1:1:1 were subjected to sensory testing in a taste test incomparison with an aqueous nicotine solution (10 mg of nicotine in 100ml of water). Example 4 shows the results of such testing.

EXAMPLE 4

[0037] Nicotine-sweetener compounds in a ratio of 1:1 and 1:2 or 1:1:1Nutrinova Nutrition Specialties & Food Ingredients GmbH - 11 - Compoundmg of 1:1 1:2 1:1:1 1:1:1 dissolved nicotine- nicotine- nicotine-nicotine- adduct acesulfame acesulfame acesulfame- acesulfame- in saltsalt saccharin aspartame 100 ml 20 31 salt salt of 35 66 water TasteImmediately Immediately Immediately Immediately sweet, initiatinginitiating initiating after marked weak strong about 10 sweetness,sweetness, sweetness, seconds, persistent, metallic, persistent,paprika- initially somewhat after 5 like sour, no bitter off minutes:taste, nicotine taste and no then taste, aftertaste, nicotine pepper-after 5 after 5 taste like mild minutes: minutes: no no nicotinenicotine taste taste

[0038] The results verify that, in contrast to the simple mixture offree nicotine with sweeteners, the unpleasant nicotine taste can bemasked by salt formation or adduct formation of nicotine withsweeteners.

[0039] Whereas in the case of the 1:1 adducts the nicotine taste can berecognized again after a relatively long residence time in the mouth,the nicotine taste in the case of 1:2 or 1:1:1 adducts of nicotine withthe respective anions of the sweeteners can surprisingly even becompletely eliminated, so that even after some minutes of residence timein the mouth no nicotine taste can be detected.

[0040] The inventive compounds are stable and do not decompose evenduring incorporation into chewing gum or other preparations suitable forwithdrawal from smoking. In particular, they can be used in intermediateproducts or precursor products without nicotine and sweetenersseparating. Therefore, they may be incorporated without problem into thepreparations with which they are to be consumed, for example chewinggum, chewing tablets, compressed compositions or other preparations fororal use.

[0041] The use is described by the following examples.

EXAMPLE 5

[0042] Incorporation into Chewing Gum

[0043] For incorporation of the inventive compounds into chewing gum,sugar-free chewing gum strips are produced from the generally knowningredients chewing gum base, sugar-free sweeteners, such as sugaralcohols and synthetic sweeteners, glycerol and flavoring substances andthe inventive compounds according to generally known technology, that isto say the ingredients are charged one after the other into the warmedchewing gum base and are incorporated uniformly. Shaping and portioningare then carried out as usual. The ingredients correspond to thosecustomarily used, that is to say in the case of sugar alcohols, forexample, sorbitol, xylitol, mannitol, maltitol, isomalt, lactitol,erythritol, mixtures of sugar alcohols and sugar alcohols in syrup form,for example sorbitol syrup and maltitol syrup. If wanted, for additionalsweetening of the chewing gums, all known sweeteners can be used, forexample acesulfame-K, aspartame, cyclamate, saccharin, thaumatinneohesperidins DC, sucralose, brazzein, neotame.

[0044] The dosage of the nicotine salts is dependent on the amount ofnicotine which is to be present in a strip of chewing gum. In orderthat, for example, 2 mg of nicotine is present in a chewing strip 3 g inmass, 6 mg of the described 1:2 salt of nicotine and acesulfamic acidmust be used or else 7.61 mg of the described nicotine-acesulfamicacid-aspartame salt. Similarly, the dosage of nicotine can be increasedby increasing the dosage of the nicotine salts.

[0045] The nicotine salts can also be incorporated into sugar-containingchewing gum formulas. For this, instead of, or together with, the sugarsubstitutes, the sugars customarily used, for example sucrose andglucose syrup are used. The resulting chewing gums have a pleasant sweettaste which, even in the case of relatively long chewing, is notreplaced by bitter taste components.

EXAMPLE 6

[0046] Incorporation into Compressed Compositions, Tablets or ChewingTablets

[0047] For incorporation of the inventive compounds into compressedcompositions, sugar-free or sugar-containing compressed compositions,tablets or chewing tablets are produced with the use of sugar-freesweeteners such as sugar alcohols and synthetic sweeteners, aids,binders and flavoring substances and the inventive compounds accordingto generally known technology, that is to say the ingredients arehomogeneously mixed one after the other and pressed to form compressedcompositions or shaped to form tablets. The ingredients correspond tothose customarily used, that is to say in the case of sugar alcohols,for example, sorbitol, xylitol, mannitol, maltitol, isomalt, lactitoland erythritol and mixtures of sugar alcohols. In the case ofsugar-containing compressed compositions and tablets, sugars, forexample sucrose, are used either exclusively or in combination withsugar alcohols. For additional sweetening of the compressed compositionsand tablets, all known intensive sweeteners can be used, for exampleacesulfame-K, aspartame, cyclamate, saccharin, thaumatin, neohesperidinsDC, sucralose, brazzein, neotame. The dosage of the nicotine salts isdependent on the amount of nicotine which is to be present in acompressed composition or a tablet. For a dose of 2 mg of nicotine in acompressed composition or a tablet, 6 mg of the described 1:2 salt ofnicotine and acesulfamic acid must be used or else 7.61 mg of thedescribed nicotine-acesulfamic acid-aspartame salt. Similarly, thedosage of nicotine can be increased by increasing the dosage of nicotinesalts.

[0048] The resulting compressed composition or tablet has a pleasantsweet taste which is not replaced by bitter taste components even in theevent of relatively long sucking or chewing.

What we claim is:
 1. A compound of nicotine and a sweetener or ofnicotine and sweeteners as well as acid-addition salt with theirphysiologically acceptable salts a physiologically acceptable acid.
 2. Acompound as claimed in claim 1 , wherein nicotine and sweetener arepresent in a molar ratio of 1:1 or 1:2, in which latter case thesweetener molecules are identical or different.
 3. A compound as claimedin claim 1 or 2 , wherein the sweetener used is acesulfame or an otheroxathiazinone sweetener, alitame, aspartame or an aspartame-likedipeptid and tripeptid, cyclamate or an other sulfamate sweetener,glycyrrhizin, neotame, saccharin or gluconic acid or theirphysiologically acceptable salts.
 4. A compound as claimed in claim 1 ,wherein the sweetener used is acesulfame or acesulfame-K alone or incombination with a further sweetener or with its physiologicallyacceptable salt.
 5. A process for producing a compound as claimed inclaim 1 , by a) reacting, in a suitable solvent, nicotine with one or 2sweeteners, which are identical or different, in the form of their freeacid and then isolating the reaction product formed, or b) reacting, ina suitable solvent, nicotine with one or 2 sweeteners, which areidentical or different, or with their physiologically acceptable saltsin the presence of a physiologically acceptable acid, and then isolatingthe reaction product formed.
 6. The process as claimed in claim 5 ,wherein water or water-miscible solvents or water and water-misciblesolvents are used as solvent.
 7. The process as claimed in claim 5 ,wherein the physiologically acceptable acid used is hydrochloric acid.8. Method of manufacturing a chewing gum by incorporating a compoundaccording to claim 1 into a chewing gum raw material.
 9. Method ofmanufacturing a chewing tablet by incorporating a compound according toclaim 1 into a chewing tablet raw material
 10. A solid or liquidpreparation, in the form of a chewing gum, a chewing tablet or acompressed composition, for the oral administration of nicotine,comprising a compound as claimed in claim 1 .